Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Therefore patients with Type 2 diabetes mellitus are at especially increased risk of macrovasuclar and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutical control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus. DPP-IV inhibitors have been found to be useful for treating diabetes, and particularly Type II diabetes.
The present invention provides novel processes for preparing 1-[2-(cyclopentylamino)acetyl]pyrrolidine-2S-carbonitrile derivatives having the structure of formula I,
which are potent dipeptidyl peptidase IV (DPP-IV) inhibitors. The structural formula I bear two stereocentres on the cyclopentane ring and one or two stereocentres on the pyrrolidine ring.
Several structural variants of 1-[2-(cyclopentylamino)acetyl]pyrrolidine-2S-carbonitrile inhibitors of dipeptidyl peptidase IV (DPP-IV) have been described in PCT Publication Nos. WO 2005/075426, 2006/011035, 2006/040625, and U.S. Pat. Nos. 7,205,323, and 7,230,002
The U.S. Pat. No. 7,205,323 specifically describes and claims compounds of general formula I and related structural variants where ‘X’ is as defined hereinafter. The method disclosed for the preparation of compounds of the general formula I, involves coupling of a cyclopentylamine derivative of the general formula II with chloroacetyl-2S-cyanopyrrolidine derivative of the general formula III.

However, this coupling reaction suffered a number of drawbacks such as formation of significant levels of impurities, incomplete reaction, moderate yield and difficulty in isolation and purification of product due to the high aqueous solubility of the product. A major impurity which was formed under described coupling conditions was characterized as the dimeric product IV formed by dialkylation of intermediate II. This also necessitates the removal of unreacted intermediate II from the product. This impurity was formed up to 10-15% when a 1:1 mixture of intermediate II and intermediate III were used in the coupling reaction. The formation of dimeric impurity may be minimized by use of excess amine intermediate II in the coupling reaction, which affected the cost of the product. The relatively nonpolar dimeric impurity IV had a lower solubility, which further complicated the purification process.

A large number of chemical transformations were required for the synthesis of intermediate II and III which affected the overall chemical yield of the product. The present invention describes a more efficient approach for the synthesis of compounds of the structural formula I in considerably fewer chemical steps and improved yields starting from commercially available (±)-2-azabicyclo[2.2.1]-hept-5-ene-3-one (Vince lactam) and a suitable proline derivative. Moreover, no chromatographic purification step is involved in the present process.
PCT Publication Nos. WO 2005/075421; 2004/099185; 2004/101514; 2003/074500 and 2004/009544; U.S. Publication No. 2004/0072892, and Japanese Publication No. JP 2004/244412, all of which are incorporated herein by reference in their entireties, disclose methods for preparing a compound of formula A described hereinafter. US 2004/0072892 and WO 2003/002553 disclose a process for the preparation of (2S,4S)-1-(bromoacetyl)-4-fluoropyrrolidine-2-carbonitrile. WO 2003/074500 discloses a process for the preparation of (2S,4S)-1-(chloroacetyl)-4-fluoropyrrolidine-2-carbonitrile. These processes for preparing compounds of formula A involve several steps, which significantly reduces the overall yield, thereby increasing their cost and time.
These processes also require tedious purification steps. In addition, the process in WO 2003/002553 utilizes diaminosulfur trifluoride (DAST) for fluorination, which is expensive and unstable at temperatures above 90° C. Furthermore, DAST is a flammable reagent with a flash point of 23° C.
Thus, the processes of the prior art present a number of practical difficulties that limit their use to relatively small scale applications. Therefore, there is a need for the development of a process which is amenable to scale-up and capable of practical application to large scale manufacturing. Understanding the importance of compounds of formula A as a key intermediate in the production of several DPP-IV inhibitors, there remains a need for alternative simple and cost-effective methods of preparing these compounds. The processes of the present invention for the preparation of a compound of formula A are convenient, efficient and easily scalable, and can function at high operative concentrations. Furthermore, the product of these processes can easily be worked up.